Page 67 - Haematologica July

Late effects after hematopoietic stem cell transplantation for thalassemia major
tion of 9 months). Forty-four patients underwent phlebotomy and/or received chelation therapy after transplant.
Definition of methods and end points
Late effects data documented by physicians were collected through visits to reference or transplant centers. Collected data included medical examination results, long-term treatment, and laboratory tests (serum ferritin, creatinine and hormone levels). Measurements of height and weight were converted to standard deviation scores (SDS) using French references.16 Delay of puberty, hypogonadism, being overweight, hypothyroidism, heart failure, and diabetes were defined using standard criteria (see Online Supplementary Methods).
Statistical analysis
Continuous variables were reported as mean±Standard Deviation (SD) or as median and interquartile range (IQR) for non- normal distribution. Wilcoxon signed rank test was used to com- pare sample median. As repeated measurements were made on the same statistical units (several measurements for each patient), univariate and multivariate linear mixed-effects models were used.17 Those variables significantly associated with outcome and those that were marginally significant (P<0.10) in univariate analy- sis were included into multivariate analysis. For all analysis, a two- tailed test was used; P<0.05 was considered significant. All statis- tical analysis was performed using IBM SPSS Statistics v.20 (IBM SPSS Inc., Chicago, IL, USA).
Results
Thyroid, diabetes and heart
Eleven patients (11%) developed thyroid complications after HSCT (Table 2). The spectrum of thyroid complica- tions was broad. Seven of 11 patients with a median serum ferritin level at transplant of 1560 mg/L had subclinical or overt hypothyroidism; this was transient in 2 cases. Two patients developed nodules or cysts without biological abnormalities and 2 other patients an autoimmune thyroid disease. Only 3 of 90 patients who received a single trans- plant with no irradiation developed permanent hypothy- roidism. No patient experienced thyroid carcinoma.
Five patients (5%) had diabetes mellitus after transplanta- tion; their median age at HSCT was 13.7 years (range 1.8- 26) and median serum ferritin level 1085 mg/L. Two patients
Table 2. Thyroid complications, diabetes and impaired cardiac function.
were treated with corticosteroids for GvHD (Table 2). One patient, with arrhythmia and cardiomyopathy before transplant, regained normal heart rhythm and func- tion after HSCT. Two patients who received a single condi- tioning with BuCy (200 mg/Kg) at the age of 13 and 4 years developed cardiac insufficiency 84 and 116 months, respec- tively, after HSCT. The first patient, now aged 39 years, has a moderate cardiac insufficiency whereas the other, who experienced a more severe disease course, is still undergo- ing treatment at the age of 20 years (Table 2). Their serum ferritin levels at HSCT were 370 and 1510 mg/L, respective- ly. No cardiac MRI was available at onset of cardiac symp- toms to allow investigation of a possible cardiac iron over-
load.
Growth
In multivariate analysis, older age at the time of trans- plantation and, to a lesser extent, higher serum ferritin lev- els inversely correlated to height SD scores after transplant (Online Supplementary Table S1). Patient’s sex was not found to affect height SDS evolution after transplantation. Height SDS also decreased with time (P<0.001). Forty-nine patients (30 females and 19 males) had reached their full-grown height at last follow up. The median SDS for final height was of -1.4 (range -3 to 1.3) in males and -1.1 (range -3 to 3) in females.
The multivariate analysis revealed that, unlike height, weight SDS increased with time (P<0.001). This increase was more prominent in females compared to males (P=0.003) (Online Supplementary Table S1). At last follow up, 36% of the 49 adult patients (11 females and 7 males) were overweight [Body Mass Inedx (BMI) >25 kg/m2]. Four adult females were obese with a BMI of over 30 kg/ m2.
Pubertal development in females
At last evaluation, 43 of 54 females were assessable for puberty. For 6 of 43 patients, puberty was reached or ongo- ing at HSCT: all had secondary amenorrhea after transplant and 5 had hypogonadism (hypergonadotropic in 4 patients). Four of 43 females had delayed puberty at HSCT: all of them subsequently developed hypogonadism.
Thirty-three of 43 females were pre-pubertal at trans- plant. One third (12 of 33) experienced spontaneous and normal puberty after one HSCT performed at a median age of 2.5 years. Only one patient had hypergonadotropic
Thyroid complications Hypothyroidism
Hashimoto disease Hyperthyroidism (Grave disease)
Hemorrhagic pseudocysts /nodules Diabetes
Impaired LVEF (≤ 50%)
Number of patients
11 7** 1* 1
2 5*
2
Median time HSCT-disease (months, range)
68 [11-164] 102
30
n=1, 226; n=1, 276 78 [3-249]
n=1, 84; n=1, 116
Conditioning
Bu-Cy, TLI (n=1) Bu-Cy Bu-Cy
TBI/Bu-Cy
Bu-Cy (n=4)° TBI (n=1)
Bu-Cy
a/c GvHD
0/0
2/1 0
Treatment
L-Thyroxin (n=7) L-Thyroxin + Surgery (n=1) Carbimazole and L-Thyroxin
Surgery (n=2)
Insulin (n=4) OAD (n=1)
ACEI (n=1) Diuretics (n=2)
HSCT: hematopoietic stem cell transplantation; a/cGvHD: acute/chronic graft-versus-host disease; Bu-Cy: busulfan and cyclophosphamide; TBI: total body irradiation; TLI: total lymphocyte irradiation; LVEF: left ventricular ejection fraction; OAD: oral anti-diabetic; irr: irradiation; ACEI: angiotensin-converting enzyme inhibitor. *Second transplant for one patient.°One patient had received irradiation for extra medullary hematopoiesis before HSCT.**Second transplant for 2 patients.
haematologica | 2018; 103(7)
1145